Glaucoma is a leading cause of blindness worldwide and continues to pose a clinical challenge. This group of diseases is characterized by the slow, progressive loss of retinal ganglion cells (RGC) and their axons, and is clinically recognized by characteristic changes to the optic nerve head and resultant visual field loss. Although there have been many improvements in the diagnosis and treatment of the disease, many aspects of its molecular pathogenesis remain unclear and loss of vision remains irreversible. Recent work indicates that the proinflammatory nature of complement can exacerbate neurodegenerative disease and is likely to elicit glial activation with potentially harmful consequences to neuronal cells. In several disease models inhibition of complement has been shown to be neuroprotective. Data from this and other laboratories has demonstrated that components of the complement system are locally synthesized early during the glaucomatous degeneration of the neural retina and that the cytolytic C5b-9 complex is formed. Complement components specifically accumulate in association with RGC. Using an ischemic model of retinal damage we have also provided functional data demonstrating that complement actively contributes to RGC loss. Finally, we present preliminary data suggesting that mutations in complement component genes contribute to the risk of developing glaucoma in humans. This application is based upon the hypothesis that complement is synthesized in response to RGC stress and actively promotes rapid RGC death, thereby limiting the period of active neuroinflammation. We further hypothesize that inhibition of the complement cascade modulates the rate and extent of RGC and axonal loss in glaucoma. Using a rodent model of ocular hypertension, cell culture, human eye donor tissue, and DNA from glaucoma patients we propose to 1) functionally test the hypothesis by inducing ocular hypertension in complement deficient mice to determine if RGC damage is mitigated 2) identify the C1q ligand on stressed RGC and 3) verify that mutations in complement component genes are associated with the development of glaucoma. This study is aimed to characterize the role of the complement system in glaucoma. These studies will also identify a genetic risk factor for the disease and determine if modulation of the complement response represents a potential neuroprotective treatment for glaucoma. PUBLIC HEALTH RELEVANCE: Project Narrative Glaucoma is a leading cause of vision loss and blindness in the industrialized world. A better understanding of the molecular events to lead to the destruction of the retina in this disease will benefit the development of novel treatment modalities. We propose to determine the functional significance of complement system activation, a recently described and potential cytotoxic process, which occurs in the glaucomatous retina.